This work is conducted under protocol 03-M-0186, NCT00060775. In this project, our group is examining biological aspects of risk for mood and anxiety disorders in children. Such work has major public impact. By identifying biological risks in children, information on novel treatments and preventative interventions will emerge. Given the understanding of most chronic mental illnesses as developmental disorders, such information holds the hope of dramatically influencing the mental well-being of many individuals. This project encompasses work examining the degree to which neurocognitive profiles vary among children and adolescents stratified with respect to personal and family history of mood and anxiety disorders. For these studies, personal history is defined based on early-childhood temperament. In a second protocol, we are acquiring fMRI data from a subset of these subjects. We have expanded our efforts in these protocols to encompass studies in juveniles across the full span of childhood and adolescence. Thus, one set of studies is based among young adults who have been prospectively followed for more than two decades. A second set of studies is based in school-aged children who are now approaching adolescence. In both sets of studies, as well as the larger series of studies in this project, considerable progress continues to be made. Studies on temperamental risk continue to dominate activities during the past year, as they had in the few years immediately prior. Thus, in this past year, as in other recent years, studies on temperament occupy more than 75% of all resources devoted to research on risk. Major questions remain on family-based associations, concerning the degree to which these associations reflect environmental, genetic, or interacting influences of genes and the environment. Of note, during the past year, we reported results from a second major follow-up of our adult cohort, replicating findings that demonstrate persistent influence of temperament on risk into young adults. This has led us to continue to shift an increasingly large proportion of our work away from studies of family-based risk to focus on temperament. We have also completed our first follow-up of the child cohort, and we plan to report results in this second cohort in the coming years. Moreover, a steady stream of brain-imaging papers has been emerging from studies based in both of these cohorts. Finally, other questions relate to the identification of factors that differentiate among children who are at high risk yet remain resilient from those who are at risk but manifest problems. Work in this project over the next few years is designed to address these questions. Problems with anxiety tend to run in families. Thus, anxiety often occurs among children born to parents with anxiety disorders as well as in children born to parents with major depressive disorder (MDD). In adults, MDD involves dysfunction in prefrontal brain regions that regulate attention to emotional stimuli. These abnormalities: i) have been found primarily in adults with specific familial forms of MDD, ii) persist after recovery from MDD, and iii) relate to anxiety. In adults, some data suggest that anxiety disorders are also associated with prefrontal dysfunction. However, findings in anxiety appear most strongly related to attention, whereas findings in MDD appear most strongly related to memory. This has stimulated attempts to dissociate factors in children associated with risk for anxiety as opposed to MDD. This protocol is attempting to dissociate these aspects of risk, through behavioral and fMRI studies of emotion regulation in high and low-risk adolescents. In general, research in this area continues to occupy a shrinking amount of resources in our group. Finally, our most in-depth studies focus on temperament, particularly the temperament of behavioral inhibition. This work is made possible through our strong collaborative relationship with Dr. Nathan Fox at the University of Maryland. Our studies in this area continued to grow and expand this year, as they had done in the immediately prior years. Dr. Fox has followed cohorts of approximately 600 infants as they passed though childhood. These children have received repeated assessments of their temperament. Temperament classifications in the sample during infancy and early childhood have been shown to predict behavior later in life. We have also completed a series of investigations in this sample. Results from these studies support the conclusions generated in other research within our group. Namely, this work establishes the presence of strong, consistent associations between the presence of and risk factors for mental illness in children and the presence of perturbed brain function. In the past year, our group continued to have significant success in charting relationships between temperament and brain function. We continue to publish widely in this area, having published seven papers in this area during the past year, and we have acquired data from many subjects during the past 12 months. During the next year, we plan to continue to report results from completed research. This includes reports on subjects who now are in their mid-20's, examining the manner in which early temperament relates to later brain function and psychopathology, expressed in early adulthood. We recently reported results from an assessment when subjects were in their early 20's, demonstrating a long-term association between temperament and risk. We also completed imaging studies in relatively large samples from this older cohort. We have published more than five brain imaging papers in this cohort, and we have many other imaging papers under review. Finally, we have completed studies in the younger cohort. This led to many papers in various stages of completion. This includes reports from studies both in late adolescents and in pre-adolescent children. Most importantly, we are in the midst of a large set of imaging studies in the younger cohort of pre-adolescents, and we reported our first results in the past year from one such study, appearing in a top-ranking journal. Overall, the results from these studies show that the seeds of temperament continue to be expressed throughout development. Behaviorally, these seeds are expressed in measures of task performance and signs of psychopathology. From a brain-function perspective, these seeds are expressed in measures of electrophysiology and fMRI. Moreover, these measures of brain function mediate and moderate the relationships between temperament and psychopathology. As such, the studies provide important information on understanding risk for psychopathology.